The Hippo-YAP signaling pathway has emerged as a major driver of tumorigenesis and metastasis in a wide spectrum of human malignancies. The distal effector of the pathway - YAP, functions as a transcriptional activator driving expression of pro-proliferation and anti- apoptotic genes. Importantly, several tumor types are YAP dependent, including colorectal, hepatocellular, meningioma, mesothelioma and schwannoma. Several studies strongly promote the notion that inhibiting the Hippo-YP pathway will show efficacy in a broad spectrum of cancer types. Our long-term goal is to identify small molecule inhibitors of the Hippo-Yap pathway that can be developed into therapeutic agents for the treatment of cancers that are Hippo- YAP dependent. To obtain potent lead compounds that selectively inhibit YAP-driven transcription we will implement an ultra High Throughput Screening campaign using the Scripps Drug Discovery Library. Identified leads will assessed in a series of secondary screens and Structure Activity Relationship analysis and medicinal chemistry will be used to optimize and prioritize leads based on their drug-like properties. Top leads will be used in mechanism of action studies and tested in cell-based models of YAP-dependent tumors including meningioma and schwannoma cells to determine the effects of select compounds on tumor cell growth and survival. The proposed research campaign will identify safe and potent lead compounds that will be tested in vivo and leads suitable for clinical development as therapeutics will be identified. These studies should result in identification of select leads demonstrating efficacy against a broad spectrum of human tumors which are YAP-dependent involvement.